Discovery of novel α-carboline derivatives as glycogen synthase kinase-3ß inhibitors for the treatment of Alzheimer's disease.
Arch Pharm (Weinheim)
; 355(10): e2200156, 2022 Oct.
Article
em En
| MEDLINE
| ID: mdl-35836098
ABSTRACT
Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease, characterized by irreversible cognitive impairment, memory loss, and behavioral disturbances, ultimately resulting in death. The critical roles of glycogen synthase kinase-3ß (GSK-3ß) in tau pathology have also received considerable attention. Based on molecular docking studies, a series of novel α-carboline derivatives were designed, synthesized, and evaluated as GSK-3ß inhibitors for their various biological activities. Among them, compound ZCH-9 showed the most potent inhibitory activity against GSK-3ß, with an IC50 value of 1.71 ± 0.09 µM. The cytotoxicity assay showed that ZCH-9 had low cytotoxicity toward the cell lines SH-SY5Y, HepG2, and HL-7702. Moreover, Western blot analysis indicated that ZCH-9 effectively inhibited hyperphosphorylation of the tau protein in okadaic acid-treated SH-SY5Y cells. The binding mode between ZCH-9 and GSK-3ß was analyzed and further clarified throughout the molecular dynamics simulations. In general, these results suggested that the α-carboline-based small-molecule compounds could serve as potential candidates targeting GSK-3ß for the treatment of AD.
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Base de dados:
MEDLINE
Assunto principal:
Doenças Neurodegenerativas
/
Doença de Alzheimer
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Neuroblastoma
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article